Principles of signaling pathway modulation for enhancing human naive pluripotency induction

被引：112

作者：

Bayerl, Jonathan ^{[1
]}

Ayyash, Muneef ^{[1
]}

Shani, Tom ^{[1
]}

Manor, Yair Shlomo ^{[1
]}

Gafni, Ohad ^{[1
]}

Massarwa, Rada ^{[1
]}

Kalma, Yael ^{[2
]}

Aguilera-Castrejon, Alejandro ^{[1
]}

Zerbib, Mirie ^{[1
]}

Amir, Hadar ^{[2
]}

Sheban, Daoud ^{[1
]}

Geula, Shay ^{[1
]}

Mor, Nofar ^{[1
]}

Weinberger, Leehee ^{[1
]}

Tassa, Segev Naveh ^{[1
]}

Krupalnik, Vladislav ^{[1
]}

Oldak, Bernardo ^{[1
]}

Livnat, Nir ^{[1
]}

Tarazi, Shadi ^{[1
]}

Tawil, Shadi ^{[1
]}

Wildschutz, Emilie ^{[1
]}

Ashouokhi, Shahd ^{[1
]}

Lasman, Lior ^{[1
]}

Rotter, Varda ^{[3
]}

Hanna, Suhair ^{[4
]}

Ben-Yosef, Dalit ^{[2
]}

Novershtern, Noa ^{[1
]}

Viukov, Sergey ^{[1
]}

Hanna, Jacob H. ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Genet, IL-7610001 Rehovot, Israel

[2] Tel Aviv Univ, Wolfe PGD Stem Cell Lab, Tel Aviv Sourasky Med Ctr,Sackler Fac Med,Sagol S, Lis Matern Hosp,Racine IVF Unit,Dept Cell & Dev B, Tel Aviv, Israel

[3] Weizmann Inst Sci, Dept Mol Cell Biol, IL-7610001 Rehovot, Israel

[4] Rambam Med Ctr, Dept Pediat, Haifa, Israel

来源：

CELL STEM CELL | 2021年 / 28卷 / 09期

基金：

欧洲研究理事会; 以色列科学基金会;

关键词：

EMBRYONIC STEM-CELLS; DNA METHYLATION; GROUND-STATE; INHIBITION; DERIVATION; LANDSCAPE; ESTABLISHMENT; MAINTENANCE; BLASTOCYST; CIRCUITRY;

D O I：

10.1016/j.stem.2021.04.001

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Isolating human MEK/ERK signaling-independent pluripotent stem cells (PSCs) with naive pluripotency characteristics while maintaining differentiation competence and (epi)genetic integrity remains challenging. Here, we engineer reporter systems that allow the screening for defined conditions that induce molecular and functional features of human naive pluripotency. Synergistic inhibition of WNT/beta-CATENIN, protein kinase C (PKC), and SRC signaling consolidates the induction of teratoma-competent naive human PSCs, with the capacity to differentiate into trophoblast stem cells (TSCs) and extraembryonic naive endodermal (nEND) cells in vitro. Divergent signaling and transcriptional requirements for boosting naive pluripotency were found between mouse and human. P53 depletion in naive hPSCs increased their contribution to mouse-human cross-species chimeric embryos upon priming and differentiation. Finally, MEK/ERK inhibition can be substituted with the inhibition of NOTCH/RBPj, which induces alternative naive-like hPSCs with a diminished risk for deleterious global DNA hypomethylation. Our findings set a framework for defining the signaling foundations of human naive pluripotency.

引用

页码：1549 / +

页数：29

共 56 条

[1] Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation [J].